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Synthesis and Biological Evaluation of Novel Resveratrol and Combretastatin A4 Derivatives as Potent Anti-Cancer Agents.

机译：新型白藜芦醇和Combretastatin A4衍生物作为强效抗癌药的合成及生物学评价。

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摘要

Resveratrol has been reported as a potential anticancer agent but cannot be used as an antitumor drug due to its chemical and metabolic instability. We have designed and synthesized 184 novel compounds related to resveratrol in an attempt to produce more potent and drug-like molecules. We have identified a tetrazole analog of resveratrol, ST-145(a) as a lead anticancer agent from the resveratrol analog series of compounds with a GI50 value of less than 10nM against almost all the human cancer cell lines in the National Cancer Institute's screening panel.;In a separate study, we tested the hypothesis that the limited bioavailability of resveratrol, can be improved by synthesizing analogs which would be glucuronidated at a lower rate than resveratrol itself. We demonstrated that ST-05 and ST-12(a) exhibit lower glucuronidation profiles when compared to resveratrol and that these synthesized stilbenoids likely represent useful scaffolds for the design of efficacious resveratrol analogs.;We have also initiated a new discovery program to identify selective CB1 and CB2 receptor ligands from a library of novel stilbene scaffolds structurally related to the resveratrol molecule. From the screened resveratrol analogs, two compounds were identified as selective CB2 and CB1 ligands. Compound ST-179 had 47-fold selectivity for CB2 (Ki = 284 nM) compared to CB1, while compound ST-160 was 2-fold selective for CB1 (Ki = 400 nM) compared to the CB2 receptor. These structural analogs have the potential for development as novel cannabinoid therapeutics for treatment of obesity and/or drug dependency.;Combretastatin A4 (CA-4) is one of the most potent antiangiogenic and antimitotic agents of natural origin. However, CA-4 suffers from chemical instability due to cis-trans isomerism in solution. To circumvent this problem, we have developed a facile procedure for the synthesis of novel 4,5-diaryl-2H-1,2,3-triazoles as CA-4 analogs to constrain the molecule to its cis-configuration. Twenty three triazoles were prepared as CA-4 analogs and submitted for anticancer screening. Among these CA-4 analogs, ST-467 and ST-145(b) can be considered as lead anticancer agents from this series, and further investigation against various cancer cell types in vivo with this class of compound may provide novel therapeutic avenues for treatment.;Keywords: combretastatin, resveratrol, triazole, tetrazole, cannabinoid.
机译：据报道白藜芦醇是一种潜在的抗癌药，但由于其化学和代谢不稳定，不能用作抗肿瘤药。我们已经设计和合成了184种与白藜芦醇有关的新型化合物，以试图产生更有效和类似药物的分子。我们在美国国家癌症研究所的筛查小组中鉴定出白藜芦醇四唑类似物ST-145（a）是白藜芦醇类似物系列化合物的GI50值小于10nM的抗癌药物在另一项研究中，我们测试了以下假设：白藜芦醇的有限生物利用度可以通过合成比白藜芦醇本身的葡糖醛酸化速率更低的类似物来改善。我们证明，与白藜芦醇相比，ST-05和ST-12（a）的葡糖醛酸苷化分布更低，并且这些合成的类胡萝卜素可能代表了用于设计有效白藜芦醇类似物的有用支架。我们还启动了一项新的发现计划，以鉴定选择性白藜芦醇。 CB1和CB2受体配体来自与结构白藜芦醇分子结构相关的新型二苯乙烯支架的文库。从筛选的白藜芦醇类似物中，鉴定出两种化合物为选择性CB2和CB1配体。与CB1相比，化合物ST-179对CB2的选择性（Ki = 284 nM）为47倍，而与CB2受体相比，化合物ST-160对CB1的选择性为2倍（Ki = 400 nM）。这些结构类似物具有开发作为治疗肥胖和/或药物依赖性的新型大麻素疗法的潜力。康贝他汀A4（CA-4）是天然来源的最有效的抗血管生成和抗有丝分裂剂之一。然而，由于溶液中的顺反异构体，CA-4遭受化学不稳定。为了解决这个问题，我们已经开发了一种简便的程序，可以合成新颖的4,5-二芳基-2H-1,2,3-三唑作为CA-4类似物，以将分子限制为顺式构型。制备了二十三种三唑作为CA-4类似物，并提交了抗癌筛选。在这些CA-4类似物中，ST-467和ST-145（b）可被视为该系列的主要抗癌药，进一步研究这类化合物在体内对各种癌细胞类型的研究可为治疗提供新的治疗途径关键字：康他汀，白藜芦醇，三唑，四唑，大麻素。

著录项

  • 作者

    Madadi, Nikhil Reddy.;

  • 作者单位

    University of Kentucky.;

  • 授予单位 University of Kentucky.;
  • 学科 Pharmaceutical sciences.;Oncology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 281 p.
  • 总页数 281
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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